BackgroundAntimetabolite chemotherapeutic agents that target cellular metabolism are widely used in the clinic and are thought to exert their anti-cancer effects mainly through non-specific cytotoxic effects. However, patients vary dramatically with respect to treatment outcome, and the sources of heterogeneity remain largely unknown.MethodsHere, we introduce a computational method for identifying gene expression signatures of response to chemotherapies and apply it to human tumors and cancer cell lines. Furthermore, we characterize a set of 17 antimetabolite agents in various contexts to investigate determinants of sensitivity to these agents.ResultsWe identify distinct favorable and unfavorable metabolic expression signatures for 5-FU and Gemcitabine. Importantly, we find that metabolic pathways targeted by each of these antimetabolites are specifically enriched in its expression signatures. We provide evidence against the common notion about non-specific cytotoxic functions of antimetabolite drugs.ConclusionsThis study demonstrates through unbiased analyses that the activities of metabolic pathways likely contribute to therapeutic response.

中文翻译：

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预测抗代谢物化疗反应的分子特征

背景以细胞代谢为靶点的抗代谢物化疗药物广泛应用于临床，被认为主要通过非特异性细胞毒作用发挥抗癌作用。然而，患者的治疗结果差异很大，异质性的来源在很大程度上仍然未知。方法在这里，我们介绍了一种计算方法，用于识别对化疗反应的基因表达特征，并将其应用于人类肿瘤和癌细胞系。此外，我们在各种情况下表征了一组 17 种抗代谢药物，以研究对这些药物的敏感性的决定因素。结果我们确定了 5-FU 和吉西他滨不同的有利和不利代谢表达特征。重要的，我们发现这些抗代谢物靶向的代谢途径在其表达特征中特别丰富。我们提供了反对关于抗代谢药物的非特异性细胞毒性功能的常见观点的证据。结论本研究通过无偏见的分析证明代谢途径的活动可能有助于治疗反应。